Synthesis-Driven Structural Revision of C5-hydroxy-cyclo (L-Pro-L-Leu) Using Electrochemical Oxidation

Although our synthetic efforts were directed toward cordysinin A, the reported natural product, the route ultimately delivered its diastereomer, (5S)-hydroxy-cyclo (L-Pro-L-Leu), whose total synthesis is described herein. The cyclo (L-proline-L-leucine) 2,5-diketopiperazine scaffold was prepared through standard solution-phase peptide coupling, followed by deprotection and intramolecular cyclization. Electrochemical oxidation at the proline C5 position generated an N-acyl iminium intermediate that was efficiently trapped by water to afford the corresponding 5-hydroxyproline derivative. However, detailed spectroscopic characterization of the synthetic product, together with comparison to the reported data for the natural isolate, revealed notable discrepancies, suggesting that the structure originally assigned to cordysinin A was likely incorrect. Our findings instead support a structural revision of cordysinin A to a regioisomer featuring hydroxylation at the proline C4 position rather than C5.